Rob Abramovitch Dept. Microbiology and Molecular Genetics Michigan State University Drug Discovery Interdisciplinary Event May 14, 2015

1. Rob Abramovitch
Dept. Microbiology and Molecular Genetics, Michigan State University
Academic drug discovery from the perspective
of a bacterial geneticist

2. Genetics driven approach to discovering new antibiotics
Wild Type Identify
Mutant
Characterize
Mutant
Genetic discovery pipeline
Identify inhibitors of
the protein of interest
Test Activity
in Cells
Identify and optimize
lead compound
Drug discovery pipeline
Pitfalls: -- Long lead time until drug discovery work begins
-- Targets with redundancy are difficult to discover with genetic approaches
-- Target pathway is recalcitrant to drug development

3. Chemical biology approach to discovering new antibiotics
Test Activity
in Cells
Identify and optimize
lead compound
Characterize compound
treated cells
Identify mutants
resistant to compound
Drug discovery pipeline
Chemical Biology pipeline
Chemical treated cell is
analogous to mutant allele
Advantages: -- Translation-driven, while still generating basic research discoveries
-- Identify targets inaccessible to standard genetic approaches
(redundant genes)

4. Acidic pH M. tuberculosis biosensor
Abramovitch et al., Mol. Micro. 2011
Acidic pH 5.7 Neutral pH 7.0
Acidic pH-sensing is essential for pathogenesis

5. Screening 890,000 compounds for inhibitors of
biosensor florescence
42,420 compounds

6. Ethoxzolamide inhibits pH-dependent biosensor
fluorescence in macrophages and attenuates virulence
Johnson et al., 2015, Antimicrobial Agents and Chemotherapy, doi: 10.1128/AAC.00719-15

7. AppliedBasic
Academic Drug Discovery
1. New knowledge
2. Innovation
3. Train new scientists
1. Impact human health
2. Economic development
3. Forging new relationships
4. New funding opportunities

8. Acknowledgements
Abramovitch Lab:
Jake Baker
Chris Colvin
Garry Coulson
Benjamin Johnson
David Needle
Javiera Ortiz
Huiqing Zheng
Robert Fillinger
Boitshoko Molefhi
Hinako Terauchi
Harvard Medical School:
Su Chiang
Doug Flood, Jen Smith
University of Notre Dame:
Patty Champion
Felix Mba Medie
Vertex Pharmaceuticals:
Christine Memmott
Christopher Locher
Funding:
Bill & Melinda Gates Foundation (OPP1059227)
Bill & Melinda Gates Foundation (OPP1119065)
NIH NIAID Great Lakes RCE (U54AI057153)
NIH NIAID (R21AI105867)
MI Innov. & Entrepreneurship (2014-00199)
MSU and AgBioResearch start up funding
Jean P. Schultz Endowed Biomedical Research
Fund at the MSU College of Human Medicine.